Treatment Of Acute Hereditary Angioedema Attacks Research Articles

National audit of a hereditary and acquired angioedema cohort in New Zealand.

Hereditary angioedema (HAE) leads to significant morbidity and mortality from unpredictable intermittent peripheral, abdominal and laryngeal swelling. Access to appropriate healthcare and effective therapies, which can prevent and treat attacks, reduce the suffering and greatly improve quality of life. Although treatments such as C1 inhibitor (Berinert), and Icatibant are available in New Zealand (Aotearoa), there are no published data available on their use. To present a national audit of HAE and acquired angioedema (AAE) in 2019. Patients were identfied and demographical and clinical data on HAE were collected retrospectively by interview and notes review. The total number of known adult (48) and children (3) HAE and AAE (3) patients is 54. Of these, 41/54 (75%) of HAE and AAE patients were recruited to the audit. Icatibant has been available for the treatment of acute HAE attacks since 2016, and is now used in 73% of HAE patients. Icatibant is also used by patients for laryngeal attacks in the community, who may not then present to hospital. Androgens are used in half of the patients as prophylaxis, but 33% of the latter were identified as not having regular liver ultrasound screening. Tranexamic acid is used as prophylaxis in one-fifth of patients. Participants have had 40 children, half of whom may be affected. Three have been diagnosed with HAE, suggesting that the majority have not yet been tested. Corrective actions arising from this audit will improve our capacity to provide long-term care for HAE patients and their families.

Recombinant Human C1 Inhibitor (rHC1INH) Is Efficacious and Well Tolerated As Prophylaxis for Prevention of Hereditary Angioedema (HAE) Attacks: A Randomized, Phase 2 Trial

rhC1INH is currently administered for the treatment of acute HAE attacks. Repeat rhC1INH treatment for recurrent attacks during open-label extension studies have maintained efficacy while being well tolerated, supporting a potential role for rhC1INH in prophylaxis. A randomized, double-blind, 3-period, crossover study was conducted in patients ≥13 years of age with functional C1INH levels <50% of normal and ≥4 HAE attacks during the previous 3 months. Patients received rhC1INH 50 IU/kg (max, 4200 IU) once or twice weekly or placebo in three, 4-week periods; each treatment was separated by 1 week and symptoms monitored by a daily diary. Primary endpoint was number of HAE attacks per 4-week period. Additional endpoints included percentage of patients with ≥25%, ≥50% (clinical response), or ≥75% reduction in number of HAE attacks versus placebo and number of days with HAE symptoms. Thirty-two patients were randomized (mean age, 45.9 years [range, 16.9–73.5 years]). Mean number of HAE attacks was reduced from 7.2 (placebo) to 4.4 (rhC1INH once weekly; P=0.0004) and 2.7 (rhC1INH twice weekly; P<0.0001). Percentage of patients with ≥25%, ≥50%, and ≥75% reduction in HAE attacks versus placebo was 64.5%, 41.9%, and 19.4% for rhC1INH once weekly and 80.6%, 74.2%, and 41.9% rhC1INH twice weekly, respectively. Number of days with HAE symptoms was lower with rhC1INH twice weekly (5.1 days) and once weekly (8.0 days) versus placebo (10.2 days). rhC1INH was efficacious for the prevention of HAE attacks and data support continued investigation of rhC1INH as prophylaxis.

Abdominal attacks and treatment in hereditary angioedema with C1-inhibitor deficiency

BackgroundHereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients.MethodsInformation collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response.ResultsForty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 × 109/L) in 23% of attacks (mean ± SD: 15.1 ± 11.27 × 109/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77±33 versus 29±65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients.ConclusionsHAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea.Trials registrationThe data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.The following trials have been registered at http://www.clinicaltrials.gov: EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).

Angioedema is not just ‘deep urticaria’ but an entity of its own

Angioedema is not just ‘deep urticaria’ but an entity of its own

Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: Open-label continuation study

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of potentially life-threatening edema. The plasma kallikrein inhibitor ecallantide is approved for treatment of acute HAE attacks. This study evaluates the efficacy and safety of ecallantide for treatment of multiple HAE episodes in the DX-88/19 (continuation) study. Patients received 30 mg of subcutaneous ecallantide for acute HAE attack symptoms, with no limit on number of episodes treated. Primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Additional end points included change in MSCS score at 24 hours, treatment outcome score (TOS) at 4 and 24 hours, and time to response. Safety parameters included adverse events. Statistical analyses were conducted on qualifying treatment episodes (those with ≥12 patients). One hundred forty-seven patients received treatment for 625 episodes; analyses were conducted through 13 treatment episodes. Across 13 episodes at 4 hours, mean change in MSCS score ranged from -1.04 to -1.36, and mean TOSs ranged from 56.2 to 79.8. Median time to onset of sustained improvement ranged from 59 to 113 minutes. There was no indication of reduced efficacy with repeated ecallantide use. No new safety signals were detected. Eight patients (5.4%) reported potential hypersensitivity reactions, six of whom met the definition of anaphylaxis based on National Institute of Allergy and Infectious Diseases criteria. Ecallantide is effective for acute recurrent HAE attacks and maintains its efficacy and safety during multiple treatment episodes in patients with HAE. Potential hypersensitivity reactions were consistent with prior reports.

Discovery and Characterization of a Fully Human Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Treatment of Plasma Kallikrein-Mediated Edema

Plasma kallikrein (pKal) is a serine protease responsible for generating the vasodilator bradykinin, and is mainly regulated by C1 inhibitor (C1-INH). Patients with hereditary angioedema (HAE) have deficient levels of functional C1-INH, leading to unpredictable attacks of debilitating edema via dysregulated pKal-mediated bradykinin generation. Inhibition of pKal is a viable therapeutic option for HAE, as demonstrated by the efficacy of ecallantide, a specific pKal inhibitor, for treatment of acute HAE attacks.

Ecallantide for treatment of acute hereditary angioedema attacks: Analysis of efficacy by patient characteristics

Hereditary angioedema (HAE) is characterized by episodic attacks of edema. HAE is caused by low levels of the protein C1 esterase inhibitor, which inhibits plasma kallikrein, the enzyme responsible for converting high-molecular-weight kininogen to bradykinin. Unregulated production of bradykinin leads to the characteristic clinical symptoms of swelling and pain. Ecallantide is a novel plasma kallikrein inhibitor effective for treatment of acute HAE attacks. This study was designed to analyze the efficacy of ecallantide for treating HAE attacks by attack location, attack severity, patient gender, and body mass index (BMI). An analysis of integrated data from two double-blind, placebo-controlled trials of ecallantide for treatment of acute HAE attacks was undertaken. For the purpose of analysis, symptoms were classified by anatomic location and, for each location, by the patient-assessed severity of the attack. Efficacy versus placebo was examined using two validated patient-reported outcomes: treatment outcome score and mean symptom complex severity score. One hundred forty-three attacks were analyzed (73 ecallantide and 70 placebo). Ecallantide was equally effective in both male and female subjects. Ecallantide had decreased efficacy for patients with BMI > 30 kg/m(2). Ecallantide showed efficacy for treatment of severe and moderate attacks, and was effective for abdominal, internal head and neck, external head and neck, and cutaneous locations. In summary, ecallantide is effective for treatment of acute HAE attacks of different symptom locations and severity; outcomes were similar for men and women. However, the standard dose was less effective for obese patients.

Successful long‐term treatment with the bradykinin B2 receptor antagonist icatibant in a patient with hereditary angioedema

Hereditary angioedema (HAE) is a rare, autosomal dominant disorder caused by a C1-esterase inhibitor (C1-INH) deficiency (type 1) or qualitative defect (type 2). It is characterized by recurrent subcutaneous or submucosal edema attacks in various organs with a frequency from a few attacks to over one hundred attacks per year. We report on the treatment of 141 attacks in a patient with hereditary angioedema with the bradykinin B2 receptor antagonist icatibant. During the entire observation period, efficacy of icatibant was maintained and not altered due to repeated administrations. No systemic or cardiovascular side affects were observed. In the present case, icatibant proved to be an effective and safe drug for the symptomatic treatment of acute HAE attacks. Its efficacy was not impaired by repeated administrations over a three-year period in this patient.

Response to ecallantide treatment of acute attacks of hereditary angioedema based on time to intervention: Results from the EDEMA clinical trials

Hereditary Angioedema (HAE) is a rare, debilitating, genetic disorder characterized by acute attacks of edema without urticaria. Ecallantide, a direct plasma kallikrein inhibitor, is approved for treatment of acute HAE attacks. This article addresses the efficacy of ecallantide in the treatment of moderate-to-severe attacks of HAE based on time to treatment. A post hoc integrated analysis of the EDEMA4 and EDEMA3-DB clinical trials was performed based on the time to patient's treatment, defined as the time from initial recognition of moderate-to-severe symptoms to dosing (cohort, 0-2, >2-4, >4-6, >6-8, and >8 hours). Mean symptom complex severity (MSCS) score and treatment outcome score (TOS) were analyzed. Complete or near-complete resolution of symptoms was assessed at 4 and 24 hours. In this analysis, 70 patients received 30 mg of subcutaneous (s.c.) ecallantide and 73 patients received placebo. Change from baseline in MSCS score and TOS at 4 hours revealed significantly better response to ecallantide versus placebo for patients treated >2-4 (n = 46; p = 0.002; p = 0.003) or >4-6 (n = 47; p = 0.044; p = 0.043) hours after symptom onset. Fewer patients were treated within 2 hours of symptom onset; for these patients (n = 10; p = 0.752; p = 0.422) treatment did not achieve statistical significance. For overall response, complete or near-complete resolution was greatest within the 0- to 2-hour cohort (71.4%). As with other therapies for HAE early ecallantide therapy is optimal. Treatment with ecallantide within 6 hours of symptom onset leads to more rapid and sustained improvement of symptoms.

Conestat alfa for the treatment of angioedema attacks

Recently, multiple C1 inhibitor (C1-INH) replacement products have been approved for the treatment of hereditary angioedema (HAE). This review summarizes HAE and its current treatment modalities and focuses on findings from bench to bedside trials of a new C1-INH replacement, conestat alfa. Conestat alfa is unique among the other C1-INH replacement products because it is produced from transgenic rabbits rather than derived from human plasma donors, which can potentially allow an unlimited source of drug without any concern of infectious transmission. The clinical trial data generated to date indicate that conestat alfa is safe and effective for the treatment of acute HAE attacks.

Ecallantide for the Treatment of Hereditary Angiodema in Adults

Hereditary angioedema (HAE) is a clinical disorder characterized by a deficiency of C1 esterase inhibitor (C1-INH). HAE has traditionally been divided into two subtypes. Unique among the inherited deficiencies of the complement system, HAE Types I and II are inherited as an autosomal dominant disorder. The generation of an HAE attack is caused by the depletion and/or consumption of C1-inhibitor manifested as subcutaneous or submucosal edema of the upper airway, face, extremities, or gastrointestinal tract mediated by bradykinin. Attacks can be severe and potentially life-threatening, particularly with laryngeal involvement and treatment of acute attacks in the United States has been severely limited. In December 2009 the FDA approved ecallantide for the treatment of acute HAE attacks. Ecallantide is a small recombinant protein acting as a potent, specific and reversible inhibitor of plasma kallikrein which binds to plasma kallikrein blocking its binding site, directly inhibiting the conversion of high molecular weight kininogen to bradykinin. Administered subcutaneously, ecallantide was demonstrated in two clinical trials, EDEMA3 and EDEMA4, to decrease the length and severity of acute HAE attacks. Although there is a small risk for anaphylaxis, which limits home administration, ecallantide is a novel, safe, effective and alternative treatment for acute HAE attacks.

Hereditary angioedema therapy: kallikrein inhibition and bradykinin receptor antagonism.

Current strategies for the treatment of hereditary angioedema (HAE) include targeted inhibition or antagonism of the contact system, which is dysregulated in HAE patients by a C1 esterase inhibitor deficiency. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a selective bradykinin-2 receptor antagonist, have recently been evaluated in clinical studies for the treatment of acute HAE attacks. Both drugs have demonstrated evidence of efficacy and safety in treating acute HAE episodes, with ecallantide approved for use in the United States and icatibant approved for use in Europe. As therapeutic options for HAE expand for both for prophylactic and acute treatment strategies, a number of patient-specific and drug-specific factors have emerged as important considerations when developing individualized HAE management plans. Optimization of HAE therapy will require further integration of new therapies into the current treatment paradigm.

Interim Results from Continuation-the Ongoing, Open-Label, Extension Study of Ecallantide for the Treatment of Acute Attacks of Hereditary Angioedema

RATIONALE: Hereditary angioedema (HAE) is a rare and potentially fatal disease characterized by unpredictable, acute swelling attacks. Interim results from the Continuation study (DX-88/19) of ecallantide, a novel plasma kallikrein inhibitor, for the treatment of acute HAE attacks are reported.

Hypersensitivity Reactions Following Ecallantide Treatment for Acute Attacks of HAE

RATIONALE: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, acute swelling attacks. Ecallantide is a novel plasma kallikrein inhibitor developed for the treatment of acute HAE attacks. The main safety issue reported during the ecallantide development program was hypersensitivity (including anaphylaxis).

Hereditary Angioedema Therapy: Kallikrein Inhibition and Bradykinin Receptor Antagonism

Current strategies for the treatment of hereditary angioedema (HAE) include targeted inhibition or antagonism of the contact system, which is dysregulated in HAE patients by a C1 esterase inhibitor deficiency. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a selective bradykinin-2 receptor antagonist, have recently been evaluated in clinical studies for the treatment of acute HAE attacks. Both drugs have demonstrated evidence of efficacy and safety in treating acute HAE episodes, with ecallantide approved for use in the United States and icatibant approved for use in Europe. As therapeutic options for HAE expand for both for prophylactic and acute treatment strategies, a number of patient-specific and drug-specific factors have emerged as important considerations when developing individualized HAE management plans. Optimization of HAE therapy will require further integration of new therapies into the current treatment paradigm.

Hereditary Angioedema Therapy: Kallikrein Inhibition and Bradykinin Receptor Antagonism

Current strategies for the treatment of hereditary angioedema (HAE) include targeted inhibition or antagonism of the contact system, which is dysregulated in HAE patients by a C1 esterase inhibitor deficiency. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a selective bradykinin-2 receptor antagonist, have recently been evaluated in clinical studies for the treatment of acute HAE attacks. Both drugs have demonstrated evidence of efficacy and safety in treating acute HAE episodes, with ecallantide approved for use in the United States and icatibant approved for use in Europe. As therapeutic options for HAE expand for both for prophylactic and acute treatment strategies, a number of patient-specific and drug-specific factors have emerged as important considerations when developing individualized HAE management plans. Optimization of HAE therapy will require further integration of new therapies into the current treatment paradigm.

Self-administration of intravenous C1-inhibitor therapy for hereditary angioedema and associated quality of life benefits

Hereditary angioedema (HAE) is often debilitating with a serious effect on quality of life (QOL). Treatment of acute HAE attacks is usually with C1 esterase inhibitor (C1-INH) concentrates; however, treatment can be delayed by patients' travel time for attending emergency units. We assessed the impact of self-administered home therapy with intravenous C1-INH concentrate on QOL in patients with HAE. Nine patients experiencing frequent or severe debilitating HAE attacks were offered self-administration of C1-INH concentrate. QOL was assessed prior to and following home therapy using the Dermatology Life Quality Index (DLQI) and 36-Item Short Form Survey (SF-36) questionnaires. Seven patients were recruited into the study. QOL was assessed at baseline and after 3 to 48 months of home therapy. The mean DLQI score fell from 12.6 +/- 4.65 to 2.7 +/- 1.38 (P < 0.001). Mean SF-36 scores for the individual and combined components also improved significantly. No serious complications were documented during a follow-up period of 27 to 72 months. Self-administration of C1-INH improved QOL on both physical and psychological parameters. Patients were able to resume a normal life without restrictions caused by the condition.

Appraisal of danazol prophylaxis for hereditary angioedema

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by painful, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. The inflammation can be disfiguring, debilitating, quite painful, and, in the case of laryngeal attacks, life-threatening. Attacks are frequently the source of unnecessary exploratory abdominal procedures, extended hospital stays affecting a patient's ability to retain employment, and severe compromise of the patient's quality of life. HAE is estimated to affect 10,000 people in the US and is caused by deficient or dysfunctional C1-inhibitor, a naturally occurring molecule that is known to inhibit kallikrein, bradykinin, and other serine proteases in plasma. The treatment and management of HAE have been hampered by the dearth of safe and effective therapies. In the United States, there are currently no approved therapies for the treatment of acute HAE attacks. Although prophylactic HAE therapies do exist, they are often viewed as suboptimal due to moderate degrees of efficacy and the existence of adverse effects associated with therapy. Danazol, an attenuated androgen, is the most commonly prescribed prophylaxis treatment for HAE in the United States. Although it has demonstrated moderate efficacy in the prevention of HAE attacks, danazol's side-effect profile can be problematic because there is a correlation between frequency and severity of adverse events and dosage and duration of therapy.

Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema

To provide a summary of the literature regarding the use of attenuated androgens during the past 40 to 50 years for the treatment of hereditary angioedema (HAE). MEDLINE and PubMed were searched to identify studies involving the treatment of HAE with androgens. Studies were selected based on their relevance to the use of androgens for the treatment of HAE. Attenuated androgens have proven successful for the short- and long-term treatment of HAE. Adverse effects are still concerning, and their use in children and pregnant women must be undertaken with great caution. Scheduled monitoring of liver function tests and lipid profiles in patients treated with these medications is critical. Attenuated androgens have been successful in the short- and long-term treatment of HAE, and they are still the most frequently used medications in the United States for the treatment of this disease. There is a lack of readily available options for the treatment of acute HAE attacks apart from the administration of fresh frozen plasma or safe prophylactic therapies; however, several appropriate agents currently in clinical trials in the United States appear promising.

Hereditary angioedema: A decade of human C1-inhibitor concentrate therapy

C1-inhibitor (C1-INH) is a serine protease inhibitor regulating the complement, kinin-kallikrein, coagulation, and fibrinolytic systems. Hereditary angioedema (HAE) is caused by an inherited deficiency of C1-INH characterized by sudden, recurrent edematous swellings of the subcutaneous or submucosal tissues. The optional therapy for the acute management of HAE is administration of human C1-INH (hC1-INH) concentrate. However, hC1-INH is not available in many countries, in which case fresh frozen plasma is an alternative. To summarize our experience with hC1-INH concentrate in patients with HAE. Clinical and laboratory information on the effectiveness and safety of hC1-INH administered to relieve 468 acute edematous attacks in 61 patients with HAE was analyzed. Severe abdominal or subcutaneous attacks and laryngeal edema were consistently relieved by the administration of 500 U hC1-INH concentrate. Symptoms improved within 15 to 60 minutes of administration. Progression of the attacks was never observed, and there were no recurrent attacks within 72 hours. hC1-INH concentrate requirements did not change after repeated use. hC1-INH concentrate proved effective in the management of 94 attacks in 22 children and 6 attacks in 4 pregnant women. Adverse reactions, viral infections, and antibody formation against the purified protein did not occur. The administration of hC1-INH concentrate in HAE is highly effective and safe for the treatment of acute attacks and short-term prophylaxis and in pediatric patients and pregnant women. Human C1-INH concentrate is effective and safe for the treatment of acute HAE attacks as well as for short-term prophylaxis.